Asthma is marked by chronic airway inflammation that if not treated, invariably leads to permanent changes in the airways and progressive loss of lung function. Airway inflammation is a complex process involving cascades of pathogenic events that begin with an initial stimulus, but is likely maintained by many factors. The goals of this program project are to study the development, maintenance, and treatment of airway inflammation and altered airway function that follows allergen sensitization and re-exposure. The three scientific projects brings together complementary approaches in both animal models and human studies to define the cellular and molecular basis for the development and persistence of asthmatic responses in the lung. The objectives include: 1) Characterize the role of airway macrophages in corticosteroid-resistant compared to corticosteroidsensitive asthma as well as the mechanisms underlying increased and chronic activation of macrophages in the corticosteroid-resistant asthmatics. 2) Defining the role of CD8+ T cells in the development and maintenance of altered airway function, lung inflammation and mucus hyperproduction and delineating the pivotal role for leukotriene B4 and the interactions with its high affinity receptor, BLT1, for lung cell accumulation and activation of CD8+/IL-13+ T cells. 3) Defining the role of persistent activation of ERK1/2 in system memory development, the means by which multiple allergen exposure evades development of tolerance, resulting in sustained airway inflammation and airway hyperresponsiveness. Together with the strong Clinical and Morphology Cores, this program brings together a group ofexperienced scientists investigating airway inflammation using multidisciplinary approaches with the objectives of defining new pathways accounting for persistent and refractory disease in chronic asthma.